To identify genes required specifically for neocortical plasticity, we will focus on the activity-dependent plasticity of responses to the two eyes in the primary visual cortex during the critical period. We will screen memory mutants selected as likely to be defective in cortical plasticity in Project 1 for deficits in this form of visual cortical plasticity. We will use monocular visual deprivation during the critical period to induce plasticity, and test the mice with microelectrode recordings and intrinsic signal optical imaging methods recently developed in our laboratory. We will then study in detail by the methods noted below mutants that affect plasticity in both somatosensory (Project 2) and visual (this project, Project 3) cortex. Therefore, we will coordinate the sequence of mutant studies in projects 2 and 3 so that mutants that do not affect either visual or somatosensory plasticity can be set aside. The next series of experiments on selected mutant genes will focus on the development of cortical maps and the receptive field properties of individual neurons. Mutations that do not perturb the early development of the cortex and visual responses but do alter cortical plasticity will be the subject of detailed analysis. We will search for the basis of of plasticity defects in the selected mutants by measuring their the effects on the turnover of dendritic spines and synaptic boutons in vivo and the change in this turnover elicited by stimuli that would normally cause plasticity of visual responses. Because the appropriate regulation of intracortical inhibition is known to be a crucial regulator of visual cortical plasticity, we will also determine the effects of selected mutations on inhibitory neurotranmission by making whole cell patch recordings in vitro. These studies will identify novel genetic pathways that are specifically involved in neocortical plasticity. Nearly all of earlier research on genes involved in forebrain plasticity has begun from defects in plasticity in the hippocampus. We are selecting mutants in which hippocampal function should be normal. Defects in neocortical plasticity are likely to underly defects in cognition and awareness that underly many forms of mental illness and neurobehavioral developmental disorders. Identification of genetic pathways in experimental animals will be a first step toward understanding them and formulating rational therapy for these afflictions.